1. Field of the Invention
The development of non-ionic water-soluble contrast media illustrated that the toxicity of triiodinated benzene moieties can be decreased dramatically. It gave birth to a new generation of contrast media, which was very important, since ionic contrast media, despite their low cost have many undesirable side effects. Since the original development of Metrizamide.RTM. efforts to develop better contrast media, both ionic and non-ionic, continued and have led to a second generation of compounds. Current ionic, monomeric contrast media are used to opacify the vascular or parenchymatic structures. With large doses of these media needed for contrast enhancement in computerized tomography and i.v. digital arteriography, the side effects become of great significance. Therefore, further improvements to decrease toxicity by developing economically feasible compounds are necessary and desirable.
In contra-distinction to the ionic contrast media materials, non-ionic contrast media have made a major contribution to the safety of the neuroradiology patient. In developing new non-ionic contrast media for vascular and urographic there is still ample room to achieve improvements as to many of the desired properties for a contrast medium. Important to an acceptable contrast medium is water solubility and low viscosity and the degree of biological inertness predicated by non-ionicity, high hydrophilicity and high iodine content and low osmolality. Since to a degree some of these properties are mutually exclusive, it is necessary to provide compromises in a final product.
In developing new products fulfilling the required properties, it is essential that processes be provided which allow for substantial flexibility in the groups attached to the aromatic ring. In addition, steps should provide for high yield, particularly in synthetic steps which appear late in the process. In addition, the materials employed should be relatively inexpensive, since contrast media are used in large amounts and, therefore, the cost of the contrast medium is a substantial factor of the cost of the diagnostic process.
2. Description of the Prior Art
U.S. Pat. No. 3,701,771, page 9, lines 70 ff, suggest substitution of the acylaminophenyl compound with allyl halide compounds to introduce a N-allylic group on the carbamoyl nitrogen, followed by permanganate oxidation to produce the dihydroxyalkyl group. U.S. Pat. No. 3,702,866 teaches the allylation of the polyiodinated acetanilide, followed by oxidation with manganese dioxide. The product is taught for use as a non-ionic contrast medium. Other patents of interest include U.S. Pat. Nos. 4,001,323, 4,021,481, 4,243,653, and 4,250,113. None of the prior art teaches use of benzamides.